The causative agent of anthrax is Bacillus anthracis, a Gram-positive spore-forming rod-shaped bacterium. The Center for Disease Control and Prevention recognizes this bacterium as a Category A agent with recognized bioterrorism potential (bt.cdc.gov/agent/anthrax/needtoknow.asp; Sep. 21, 2006).
Anthrax is a serious disease and can be contracted by cutaneous exposure, ingestion, or inhalation, leading to cutaneous, gastrointestinal and inhalational disease, respectively. Cutaneous anthrax occurs when spores gain access through a cut or abrasion in the skin. The organisms germinate and produce toxins that result in a local reaction with swelling and eschar formation. The disease may progress to bacteremia, and mortality is reported in up to 20 percent of untreated cutaneous cases. Cutaneous anthrax can be recognized clinically, and morbidity and mortality are low with appropriate antimicrobial therapy. Gastrointestinal disease is usually associated with the ingestion of anthrax-contaminated meat. Gastrointestinal disease can be prevented through the effective inspection of livestock and meat products entering the marketplace. Inhalational anthrax follows aerosolized exposure to the spores of B. anthracis with subsequent germination of the spores, toxin production, and invasion of the tissues and blood stream by the organism. After a usual incubation period of 2 to 6 days, exposed individuals develop symptomatic disease with very high mortality.
Of the routes of exposure, inhalation anthrax poses the highest mortality rate at approximately 40-80% (Jernigan et al. Emerg Infect Dis. 2001. 7(6):933-944; Meselson et al. Science 1994. 266:1202-1208). As such, inhalation of anthrax spores it is the most likely exposure route to be exploited in warfare or during a terrorist attack.
Three types of antibiotics are approved for anthrax: a fluoroquinolone (ciprofloxacin), tetracyclines (including doxycycline), and β-lactams (penicillin). These chemotherapies are most effective when given immediately following exposure to B. anthracis spores; longer delays before initiation of therapy is correlated with worsened outcome. For inhalation anthrax, patients are typically prescribed one or two additional antibiotics, which might include rifampin, vancomycin, penicillin, ampicillin, chloramphenicol, imipenem, clindamycin, or clarithromycin. Initial treatment is by vein (intravenous, or IV), followed by medication by mouth. A course of ciprofloxacin therapy lasting 60 days is the current standard of care for anthrax post-exposure prophylaxis. Other studies recommend even longer courses of antibiotic therapy, at least four months in duration, to reduce the risk of mortality following exposure to significant levels of the organism (Brookmeyer et al. Proc Natl Acad Sci USA. 2003. 100:10129-10132). These long durations of therapy are associated with patient non-compliance and failure to receive the entire prescribed dose (Brookmeyer et al., ib.). The pharmacokinetics of these antibacterial agents typically impose twice-daily (or even more frequent) dosing to maintain drug at adequate (protective) levels. Fatalities have occurred despite the administration of antibiotics to patients exposed to B. anthracis bacteria (Jernigan et al., ib.).
The possibility of emerging natural resistance or “engineered” resistance in B. anthracis is also an area of great concern (Inglesby et al. 2002. J. Am. Med. Assoc. 287:2236-2252). For example, although penicillin has long been considered the treatment of choice for anthrax, numerous reports of β-lactamase-producing strains, and treatment failures have appeared in the literature (Bradaric and Punda-Polic 1992. Lancet 340:306-307; Doganay and Aydin, 1991. Scand J Infect Dis. 23:333-335; Gold 1955. Arch. Intern. Med. 96:387-396; Lightfoot et al. 1990. Salisbury Med. Bull. 68 (Suppl): 95-98). Additionally, two open reading frames coding for β-lactamases have been identified in the B. anthracis genome (Chen et al. 2004. Antimicrob. Agents Chemother. 48:4873-4877; Materon et al. 2003. Antimicrob. Agents Chemother. 47:2040-2042). More recently, several reports of B. anthracis resistance to ciprofloxacin, macrolides, and tetracyclines have appeared in the literature (Brook et al. 2001. Int. J. Antimicrob. Agents 18:559-562; Choe et al. 2000. Antimicrob. Agents Chemother. 44:1766; Price et al. 2003. Antimicrob. Agents Chemother. 47:2362-2365). With the added concern of engineered resistance in a biological threat setting (Leitenberg, 1993. Biologicals 212:187-191; Pile et al. 1998. Arch. Itern. Med. 158:429-434), it becomes important to assess the spectrum of antibiotics available for treatment.
The current inhalation anthrax animal model for antibiotic testing utilizes rhesus monkeys that are both expensive and in short supply (Friedlander et al. 1993. J. Inf. Dis. 167:1239-1242). The use of a small rodent model both decreases the cost per antibiotic test and increases the number of animals per test group as well as the number of antibiotics that can be tested at any given time. The application of pre-determined dose and schedule based on “murine” infection modeling has been shown to greatly expand the utility of these small animal models and allow testing of “humanized” dosing for success or failure prior to the more expensive and difficult non-human primate models (Deziel et al. 2005. Antimicrob. Agents Chemother. 49:5099-5106).
The current standard of care for treatment of anthrax is thus lengthy, inconvenient, and not entirely effective, and alternative compounds for use in the treatment, as well as prophylaxis and prevention, of anthrax are needed. In particular, alternative compounds for use in the treatment, prophylaxis and prevention of inhalation anthrax are needed.